(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(10) International Publication Number
`WO 2018/209051 Al
`
`= a
`
`WIPO! PCT
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`15 November 2018 (15.11.2018)
`
`(51) International Patent Classification:
`A61K 9/00 (2006.01)
`A61K 47/18 (2006.01)
`A6LK 9/08 (2006.01)
`A61K 31/46 (2006.01)
`A61K 47/38 (2006.01)
`A61P 27/02 (2006.01)
`
`(21) International Application Number:
`
`PCT/US2018/032017
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`10 May 2018 (10.05.2018)
`
`English
`
`English
`
`(30) Priority Data:
`62/505,027
`
`11 May 2017 (11.05.2017)
`
`US
`
`1019 Route
`[US/US];
`(71) Applicant: NEVAKAR INC.
`202/206, Bldg. K, Bridgewater, New Jcrscy 08807 (US).
`
`(72)
`
`Inventors: PURI, Navneet; 40 Still Hollow Road,
`Lebanon, New Jersey 08833 (US). AKASAPU, Prem Sa-
`gar; 906 Rivendell Way, Edison, New Jersey 08817 CUS).
`MOHAMMED,Irfan A.; 1900 Frontage Road, Apt. 1113,
`Cherry Hill, New Jersey 08034 (US). SOPPIMATH, Ku-
`maresh; 97 Autumn Lane, Skillman, New Jersey 08558
`(US). ILITCHEY,Iouri V.; 21 Reed Road, Hillsborough,
`
`New Jersey 08844 (US). ZHANG,Tao; 52 Douglas Drive,
`Towaco, New Jersey 07082 (US).
`
`(74) Agent: FESSENMAIER, Martin; Umberg Zipser LLP,
`1920 MainStreet, Suite 750, Irvine, California 92614 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO,AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW,BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID,IL,IN,IR, IS, JO, JP, KE, KG, KH, KN,KP,
`KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG,NI, NO, NZ,
`OM,PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
`SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM,KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE,ES, FIL, FR, GB, GR, HR, HU,IE,IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO,PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW,
`KM,ML, MR, NE, SN, TD, TG).
`
`(54) Title: ATROPINE PHARMACEUTICAL COMPOSITIONS
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`(57) Abstract: The inventive subjcct matter is directed to composi-
`tions and methods for sterile and storage stable low-dose atropine
`formulations with improved stability. Most preferably, the compo-
`sitions presented hercin are substantially preservative free and cx-
`hibit less than 0.35% tropic acid from degradation of atropine. Ad-
`vantageously, contemplated formulations are also substantially free
`of preservatives.
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`[Continued on next page]
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` STERILE FILTR
`1a BAS
`poe. PES
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`FILLING
`Target RE Vecurra’ 0. 38%.q 30
`BES amovic
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`Figure 1
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`wo2018/209051A1IIITNIIIINITANTCINNNRI00TAIA
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`

`

`WO 2018/209051 AD [IAIN TNTMATAOT TN TUT AATEITT AATTA
`
`Published:
`
`— with international search report (Art. 21(3))
`— with amended claims (Art. 19(1))
`
`

`

`WO 2018/209051
`
`PCT/US2018/032017
`
`ATROPINE PHARMACEUTICAL COMPOSITIONS
`
`[0001] This application claims priority to a copending USprovisional application with serial
`
`number 62/505,027, which was filed May 11, 2017.
`
`Field of the Invention
`
`[0002] The field of the invention is pharmaceutical compositions comprising atropine sulfate,
`
`especially as it relates to various storage stable, ready-to-use, preservative free compositions,
`
`and method of manufacturing such compositions.
`
`Background
`
`[0003] The background description includes information that may be useful in understanding
`
`the present invention. It is not an admission that any of the information provided herein is
`
`prior art or relevant to the presently claimed invention, or that any publication specifically or
`
`implicitly referencedis priorart.
`
`[0004] All publications and patent applications herein are incorporated by reference to the
`
`same extent as if each individual publication or patent application were specifically and
`
`individually indicated to be incorporated by reference. Where a definition or use of a term in
`
`an incorporated reference is inconsistent or contrary to the definition of that term provided
`
`herein, the definition of that term provided herein applies and the definition of that term in
`
`the reference does not apply.
`
`[0005] Atropine is the tropine ester of tropic acid and is generally available as the sulfate salt.
`
`Nonenzymatic spontaneous hydrolysis of aqueousatropine yields tropine and tropic acid that
`
`are nontoxic but do not have biological activity in ophthalmic use. Stability has been tested,
`
`for example, for certain injectable formulations and degradation was observed over time for
`
`in-date and out-of-date formulations (4cad Emerg Med April 2004, Vol. 11, No. 4:329-334).
`
`Notably, atropine loss was significant in most cases, but less than 25% ofthe starting
`
`concentration. However, these formulations included atropine at high concentrations between
`
`0.4 mg/ml and 2 mg/ml and had a very low pH (typically equal or less than pH4 ), whichis in
`
`most cases unsuitable for ophthalmic use.
`
`[0006] In ophthalmic use, atropine is marketed as Atropine Care (Akorn) formulated as a 1%
`
`drug solution for treatment of amblyopia and further contains 0.01% w/w of the preservative
`
`benzalkonium chloride. In another indication, atropine has also been used in several pediatric
`
`1
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`WO 2018/209051
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`PCT/US2018/032017
`
`studies to slow down the progression of myopia. More specifically, children who received
`
`topically administered atropine drops had a slower disease progression than a control group
`
`in the same study. Advantageously, children receiving eye drops containing low atropine
`
`concentrations(e.g., in the range of 0.01-0.05%% w/v (0.01% w/w)) had significantly less
`
`photophobia andother side effects (see e.g., Ophthalmology, 2015:1-9). Indeed, the use of
`
`low-dose (7.e., 0.01%) atropine has becomea preferred treatment of choice in slowing the
`
`progression of myopia. Unfortunately, the toxic effects of benzalkonium chloride have been
`
`demonstrated in the lab and in the clinic, and include tear film instability, loss of goblet cells,
`
`conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier,
`
`and damage to deeper oculartissues (see e.g., Prog Retin Eye Res. 2010 Jul 29(4):312-34).
`
`[0007] In still further known compositions and methods, atropine formulations are described
`
`in WO 2017/204262 that include various buffer ingredients and water soluble polymers in
`
`which most formulations had a pH of about 4.3, 4.5, or 5.0 at an atropine concentration of
`
`0.01% w/w. While such formulations were shown to reduce progression of myopia without
`
`exacerbating mydriatic action of atropine, stability of atropine as measured by an increase in
`
`tropic acid was less than desirable within as little as four weeks.
`
`[0008] As normal tears have a pH of about 7.4, an ophthalmic solution should have the same
`
`pHas the lacrimal fluid. However, this is a challenge for an ophthalmic solutions containing
`
`atropine sulfate, as atropine sulfate is subjected to a greater degree of hydrolysis in solutions
`
`that are closer to neutral and basic pH conditions. Thus, atropine is more stable in ophthalmic
`
`solutions with a more acidic pH. For example, Atropine Care with a 1% w/w concentration of
`
`atropine is maintained at pH 5.5, but the shelf life is still limited to 15 months. Moreover, the
`
`degradation of atropine to tropic acid in aqueous solution is notably accelerated with reduced
`
`concentrations of atropine (e.g., US 9421199), which still further compoundsstability issues,
`
`particularly in low-dose atropine formulations.
`
`[0009] To reduce hydrolytic degradation, water in low-dose atropine formulations can beat
`
`least in part replaced with deuterated (heavy) water as is described in the US 9421199 patent.
`
`While conceptually attractive to use kinetic isotope effects in stability, various disadvantages
`
`nevertheless remain. Among other things, at least some of the formulations of the ‘199 patent
`
`still contained a preservative. Moreover, deuterated wateris still known to be subject to H/D
`
`exchange, and as such delivers deuterium to a subject receiving such formulations.
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`

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`WO 2018/209051
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`PCT/US2018/032017
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`[0010] Alternatively, atropine may also be delivered at reduced concentrations from a cross-
`
`linked non-degradable polymer matrix as is described in US 2016/0338947. Unfortunately, to
`
`maintain the polymer away from the cornea, a shaped implant must be worn on thesclera that
`
`is typically not well tolerated or may produce discomfort.
`
`[0011] Therefore, there is a need for improved storage stable ready-to-use compositionsthat
`
`contain atropine at low concentrations, have a physiologically desirable pH, and preferably
`
`do not contain a preservative.
`
`Summary of the Invention
`
`[0012] The inventive subject matter is directed to ready-to-use atropine compositions having
`
`improvedstability and a physiologically acceptable pH. Most preferably, such compositions
`
`are also substantially preservative free.
`
`[0013] In one aspect of the inventive subject matter, the inventors contemplate a liquid
`
`storage-stable low-dose ophthalmic atropine composition that comprises an aqueoussolution
`
`comprising a buffer, a tonicity agent, a viscosity modifier, and atropine or a pharmaceutically
`
`acceptable salt thereof, wherein the atropine or the pharmaceutically acceptable salt thereofis
`
`present in the ophthalmic atropine composition in an amount of equal or less than 0.05 wt%,
`
`wherein the buffer has a concentration of equal or less than 75mM, and wherein the
`
`ophthalmic atropine composition has a pH of between 5.0 and 6.0, and wherein the
`
`ophthalmic atropine composition is formulated such that after storage over at least two
`
`months at 25 °C and 60% relative humidity equal or less than 0.35% tropic acid is formed
`
`from degradation ofthe atropine.
`
`[0014] Preferably, atropine or the pharmaceutically acceptable salt thereof is atropine sulfate,
`
`and is present in the ophthalmic atropine composition in an amount of equal or less than 0.02
`
`wt%, or in an amount of equal or less than 0.01 wt%, or in an amount of between 0.01% and
`
`0.05 wt%, or in an amount of between 0.001 wt% and 0.01 wt%. Most typically, the buffer
`
`has a concentration of equal or less than 60mM,or equal or less than 50mM. It is further
`
`contemplated that the buffer comprises monobasic and dibasic sodium phosphate.
`
`In further
`
`embodiments, the composition will further comprise a chelator, typically a bicarboxylic acid,
`
`a tricarboxylic acid, or an aminopolycarboxylic acid, and the chelator is present in the
`
`ophthalmic atropine composition in an amount of equal or less than 0.01w %.
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`

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`WO 2018/209051
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`PCT/US2018/032017
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`[0015] Additionally, it is contemplated that the ophthalmic atropine composition has a pH of
`
`5.0 (+/- 0.2), or has a pH of 5.5 (+/- 0.2), or has a pH of 6.0 (+/- 0.2). The tonicity agentis
`
`preferably a pharmaceutically acceptable salt that is present in the ophthalmic atropine
`
`composition in an amount of between 0.2 wt% and 0.8 wt%. In still further embodiments, the
`
`viscosity modifier is a modified cellulose, and preferably a hydroxyethyl cellulose, a
`
`hydroxypropyl! cellulose, or a hydroxypropyl methylcellulose. Moreover,it is generally
`
`preferred that the ophthalmic atropine composition is substantially free of a preservative.
`
`[0016] Therefore, the inventors also contemplate a liquid storage-stable low-dose ophthalmic
`
`atropine composition that consists essentially of an aqueous solution comprising a buffer, a
`
`tonicity agent, a chelator, a viscosity modifier, and atropine or a pharmaceutically acceptable
`
`salt thereof. In such compositionsit is preferred that the atropine or the pharmaceutically
`
`acceptable salt thereof is present in the ophthalmic atropine composition in an amount of
`
`equal or less than 0.05 wt%,that the buffer has a concentration of equal or less than 75mM,
`
`and that the ophthalmic atropine composition has a pH of between 5.0 and 6.0. Moreover,
`
`such ophthalmic atropine compositions are formulated such that after storage over at least
`
`two months at 25 °C and 60% relative humidity equal or less than 0.35% tropic acid is
`
`formed from degradation of the atropine.
`
`[0017] Most typically, the atropine or the pharmaceutically acceptable salt thereof is atropine
`
`sulfate, and the atropine or a pharmaceutically acceptable salt thereof is present in the
`
`ophthalmic atropine composition in an amount of equal or less than 0.02 wt%, or in an
`
`amount of equal or less than 0.01 wt%, or in an amount of between 0.001 wt% and 0.01 wt%.
`
`In some embodiments, the buffer has a concentration of equal or less than 60mM,or has a
`
`concentration of equal or less than 50mM.it is further contemplated that the buffer comprises
`
`monobasic and dibasic sodium phosphate. The chelatoris typically a bicarboxylic acid, a
`
`tricarboxylic acid, or an aminopolycarboxylic acid. For example, suitable chelators include
`
`ethylenediaminetetraacetic acid (EDTA), typically present in the ophthalmic atropine
`
`composition in an amountof equal or less than 0.01 wt%.
`
`[0018] In other embodiments, the ophthalmic atropine composition has a pH of between 5.0
`
`(+/- 0.2) and 5.5 (+/- 0.2), or has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2), and/or the
`
`tonicity agent is a pharmaceutically acceptable salt that is present in the ophthalmic atropine
`
`composition in an amount of between 0.2 wt% and 0.8 wt%. Suitable viscosity modifiers
`
`include a hydroxyethyl! cellulose, a hydroxypropyl! cellulose, and a hydroxypropyl!
`
`A
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`

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`WO 2018/209051
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`PCT/US2018/032017
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`methylcellulose. Most typically, the ophthalmic atropine composition is substantially free of
`
`a preservative.
`
`[0019] For example, contemplated compositions include those in which the atropine or a
`
`pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in
`
`an amount of between 0.001 wt% and 0.01 wt%, wherein the buffer comprises monobasic
`
`and dibasic sodium phosphate and has a concentration of equal or less than 50mM, wherein
`
`the viscosity modifier is a hydroxyethyl cellulose, a hydroxypropy! cellulose, or a
`
`hydroxypropyl methylcellulose, and wherein the ophthalmic atropine composition is
`
`substantially free of a preservative. In other examples, contemplated compositions include
`
`those in whichthe atropine or a pharmaceutically acceptable salt thereof is present in the
`
`ophthalmic atropine composition in an amount of between 0.01 wt% and 0.05 wt%, wherein
`
`the buffer comprises monobasic and dibasic sodium phosphate and has a concentration of
`
`equal or less than 50mM, wherein the viscosity modifier is a hydroxyethyl!cellulose, a
`
`hydroxypropyl!cellulose, or a hydroxypropyl methylcellulose, and wherein the ophthalmic
`
`atropine composition is substantially free of a preservative.
`
`[0020] Viewed from a different perspective, the inventors also contemplate a storage-stable
`
`preservative-free ophthalmic atropine composition that comprises an aqueoussolution
`
`comprising low-dose atropine or a pharmaceutically acceptable salt thereof, a low-strength
`
`buffer, a pharmaceutically acceptable salt, and a cellulosic viscosity modifier, wherein the
`
`low-strength buffer has a concentration of equal or less than 50mM, and wherein the low-
`
`dose atropine is present at a concentration of equal or less than 0.05 wt%, and wherein the
`
`ophthalmic atropine composition is substantially free of a preservative.
`
`[0021] For example, the low-dose atropine in such compositions 1s present at a concentration
`
`of equal or less than 0.01 wt%, or is present in the ophthalmic atropine composition in an
`
`amount of between 0.01% and 0.02 wt%, or is present in the ophthalmic atropine
`
`composition in an amount of between 0.001 wt% and 0.01 wt%. Most typically, the atropine
`
`or a pharmaceutically acceptable salt thereof is atropine sulfate, and/or the low-strength
`
`buffer comprises a first and a second buffer component(e.g., monobasic and dibasic sodium
`
`phosphate). Mosttypically, the ophthalmic atropine composition has a pH of between 5.0 and
`
`6.0, or a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2). Contemplated compositions will
`
`typically also include a chelator(e.g., a bicarboxylic acid, a tricarboxylic acid, an
`
`aminopolycarboxylic acid) that is preferably present in an amountof 0.01 wt% (+/- 20% abs.).
`
`5
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`WO 2018/209051
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`PCT/US2018/032017
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`It is further contemplated that the pharmaceutically acceptable salt is present in the
`
`ophthalmic atropine composition in an amount of between 0.2 wt% and 0.8 wt%, or in an
`
`amount of 0.5 wt% (4+/- 0.2 wt%).
`
`[0022] Preferred cellulosic viscosity modifiers include a hydroxyethyl! cellulose, a
`
`hydroxypropyl!cellulose, or a hydroxypropyl methylcellulose, typically present in an amount
`
`of 0.5 wt% (4+/- 0.1 wt%) of the ophthalmic atropine composition. In preferred embodiments,
`
`the ophthalmic atropine composition is formulated such that after storage overat least two
`
`months at 25 °C and 60% relative humidity equal or less than 0.35% tropic acid is formed
`
`from degradation ofthe atropine.
`
`[0023] For example, in contemplated compositions the atropine or a pharmaceutically
`
`acceptable salt thereof is present in the ophthalmic atropine composition in an amount of
`
`between 0.001 wt% and 0.01 wi%, wherein the low-strength buffer comprises monobasic and
`
`dibasic sodium phosphate, and wherein the ophthalmic atropine composition has a pH of
`
`between 5.5 (4+/- 0.2) and 6.0 (4+/- 0.2). In another example, the atropine or a pharmaceutically
`
`acceptable salt thereof is present in the ophthalmic atropine composition in contemplated
`
`compositions is present in an amount of between 0.001 wt% and 0.01 wt%, wherein the
`
`ophthalmic atropine composition further comprises a chelator in an amount of 0.01wt% (+/-
`
`20% abs.) of the ophthalmic atropine composition, and wherein the ophthalmic atropine
`
`composition has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2). Alternatively, the low-
`
`strength buffer in contemplated compositions comprises monobasic and dibasic sodium
`
`phosphate, wherein the composition further comprises a chelator in an amount of 0.01 wt%
`
`(+/- 20% abs.) of the ophthalmic atropine composition, wherein the ophthalmic atropine
`
`composition has a pH of between 5.5 (+/- 0.2) and 6.0 (4/- 0.2), wherein the salt is present in
`
`the ophthalmic atropine composition in an amount of 0.5 wt% (+/- 0.2 wt%), and wherein
`
`the cellulosic viscosity modifier is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the
`
`ophthalmic atropine composition.
`
`[0024] In still another aspect of the inventive subject matter, the inventors also contemplate a
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`method of increasing storage stability of atropine in a liquid low-dose ophthalmic
`
`formulation. Typical low-doses are between 0.01 wt% and 0.02 wt%, or between 0.001 wt%
`
`and 0.01 wt%, or equal or less than 0.01 wt% of the ophthalmic formulation. Preferred
`
`methods will include a step of formulating an aqueous solution with a low-strength buffer
`
`system that includes a first and second buffer component, wherein the low-strength buffer
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`6
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`system has a concentration of equal or less than 75mM buffer, and a further step of including
`
`into the aqueous solution a pharmaceutically acceptable salt, a viscosity modifier, and a
`
`chelator. In still another step, atropine or a pharmaceutically acceptable salt thereof is
`
`included into the formulation at a low dose (e.g., equal or less than 0.05 wt% of the
`
`ophthalmic formulation), and the pH of the ophthalmic formulation is adjusted to a pH
`
`between 5 and 6. Preferably, the ophthalmic formulation is formulated such that after storage
`
`over at least two monthsat 25 °C and 60% relative humidity equal or less than 0.35% tropic
`
`acid is formed from degradation of the atropine.
`
`[0025] For example, the first and second buffer components are monobasic and dibasic
`
`sodium phosphate, respectively, and the low-strength buffer system has a concentration of
`
`equal or less than 50mM buffer. Additionally, it is contemplated that the pharmaceutically
`
`acceptable salt is sodium chloride, typically present in the ophthalmic atropine composition
`
`in an amount of 0.5 wt% (+/- 0.2 wt%) of the ophthalmic formulation. Moreover, it is
`
`preferred that the chelator is a bicarboxylic acid, a tricarboxylic acid, or an
`
`aminopolycarboxylic acid (e.g., EDTA), preferably in an amount of 0.01 wt% (4+/- 20% abs.)
`
`of the ophthalmic formulation.
`
`[0026] In other embodiments, the viscosity modifier is a cellulosic viscosity modifier, such as
`
`a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.
`
`Most typically the cellulosic viscosity modifier is present in an amount of 0.5 wt% (+/- 0.1
`
`wt%) of the ophthalmic formulation. In still further embodiments, the cellulosic viscosity
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`modifier is prepared as a separate solution, and combined with the aqueous solution
`
`containing the buffer system, the pharmaceutically acceptable salt, the viscosity modifier, the
`
`chelator, and the atropine or the pharmaceutically acceptable salt thereof. Where desired, the
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`aqueous solution is formulated using deoxygenated water. Most typically, the pH of the
`
`formulation is between 5.5 (+/- 0.2) and 6.0 (+/- 0.2), and the atropine or a pharmaceutically
`
`acceptable salt thereof is atropine sulfate. Preferably, contemplated methods also include a
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`step of sterilizing the ophthalmic formulation, and especially sterile filtration. As desired, the
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`ophihalmic formulation is then filled into a single-use or multi-dose container.
`
`[0027] Additionally, the inventors also contemplate a method of preparing a storage stable
`
`liquid low-dose atropine ophthalmic formulation that includes the steps of formulating in a
`
`first container a low-strength buffer low-dose atropine solution, and subjecting the low-
`
`strength buffer low-dose atropine solution to sterile filtration to obtain a sterile low-strength
`
`7
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`WO 2018/209051
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`PCT/US2018/032017
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`buffer low-dose atropine solution, wherein the low-strength buffer has a first and a second
`
`buffer component that form a low-strength buffer system having a concentration of equal or
`
`less than 75mM in the ophthalmic formulation, wherein the atropine is present in an amount
`
`of equal or less than 0.05 wt% of the ophthalmic formulation, and wherein the low-strength
`
`buffer low-dose atropine solution further comprises a tonicity agent and a chelator. In
`
`another step, a polymersolution is formulated in a second container, and the polymer solution
`
`is sterilized in a process other than sterile filtration (e.g., autoclaving) to so obtainasterile
`
`polymersolution. Most typically, the polymer solution comprises a polymer to modify
`
`viscosity of the low-strength buffer low-dose atropine solution upon combination. In yet
`
`anotherstep, the sterile low-strength buffer low-dose atropine solution andthesterile
`
`polymersolution are combined to obtain a sterile liquid low-dose ophthalmic formulation.
`
`[0028] Typically, the first and second buffer components are monobasic and dibasic sodium
`
`phosphate, respectively, and/or the low-strength buffer system has a concentration of equal or
`
`less than 50mM buffer in the ophthalmic formulation. The atropine is typically present in an
`
`amount of between 0.01 wt% and 0.02 wt%, or between 0.001 wt% and 0.01 wt%, or equal
`
`or less than 0.01 wt% of the ophthalmic formulation. Most preferably, the tonicity agent is a
`
`pharmaceutically acceptable salt, typically sodium chloride in an amount of 0.5 wt% (+/- 0.2
`
`wt%) of the ophthalmic formulation. Moreover, the chelatoris typically a bicarboxylic acid, a
`
`tricarboxylic acid, or an aminopolycarboxylic acid (e.g., EDTA), preferably in an amountof
`
`0.01wt% (+/- 20% abs.) of the ophthalmic formulation.
`
`[0029] It is still further contemplated that the polymeris a cellulosic polymer, and especially
`
`a hydroxyethyl! cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.
`
`Preferably, the cellulosic polymeris present in an amount of 0.5 wt% (+/- 0.1 wt%) of the
`
`ophthalmic formulation, and/or the pH of the low-strength buffer low-dose atropine solution
`
`1s adjusted to a pH between 5 and 6, or between 5.5 (+/- 0.2) and 6.0 (+/- 0.2).
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`[0030] In further embodiments, the step of combining comprises mixingthe sterile low-
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`strength buffer low-dose atropine solution and the sterile polymer solution for at least 30
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`minutes, and optionally further comprises a step offilling the ophthalmic formulation into a
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`multi-dose container. Preferably, the ophthalmic formulation is formulated such that after
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`storage overat least two months at 25 °C and 60% relative humidity equal or less than 0.35%
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`tropic acid is formed from degradation of the atropine.
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`[0031] Consequently, the inventors also contemplate a treatment kit for treatment of myopia
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`that includesa first container that contains a liquid storage-stable low-dose atropine
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`ophthalmic formulation, wherein the first container is configured as a disposable single-use
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`container or a multi-dose container, and a second container enclosing the first container,
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`wherein the liquid storage-stable low-dose atropine ophthalmic formulation comprises an
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`aqueous solution comprising a buffer, a tonicity agent, a viscosity modifier, and atropine or a
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`pharmaceutically acceptable salt thereof, wherein the atropine or the pharmaceutically
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`acceptable salt thereof is present in the ophthalmic atropine composition in an amount of
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`equal or less than 0.05 wt%, wherein the buffer has a concentration of equal or less than
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`75mM,and wherein the ophthalmic atropine composition has a pH of between 5.0 and 6.0,
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`and wherein the ophthalmic atropine composition 1s formulated such that after storage over at
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`least two months at 25 °C and 60% relative humidity equal or less than 0.35% tropic acid is
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`formed from degradation of the atropine.
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`[0032] For example, in some embodiments, the first container 1s a blow-fill-seal (BSF)
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`container and/or the second containeris a laminated metallized pouch. In other embodiments,
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`the atropine or pharmaceutically acceptable salt thereof is present in the ophthalmic atropine
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`composition in an amount of equal or less than 0.01 wt%, or in an amount of between 0.01
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`wt% and 0.05 wt%, or in an amountof between 0.001 wt% and 0.01 wt%. Mostpreferably,
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`the buffer has a concentration of equal or less than 75mM,or equal or less than 50mM.For
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`example, preferred buffers comprise monobasic and dibasic sodium phosphate, and may
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`further comprise a chelator(e.g., a bicarboxylic acid, a tricarboxylic acid, or an
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`aminopolycarboxylic acid such as EDTA)that is present in the ophthalmic atropine
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`composition in an amountof equal or less than 0.01 wt%.
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`[0033] Most typically, the ophthalmic atropine composition has a pH of 5.0 (+/- 0.2), or a pH
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`of 5.5 (4/- 0.2), or a pH of 6.0 (4/- 0.2), and it is further contemplated that the tonicity agent
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`is a pharmaceutically acceptable salt that is present in the ophthalmic atropine composition in
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`an amountof between 0.2 wt% and 0.8 wt%. Preferred viscosity modifiers are modified
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`celluloses such as a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl
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`methylcellulose. Still further, it is preferred that the ophthalmic atropine composition is
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`substantially free of a preservative.
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`[0034] Various objects, features, aspects and advantages of the inventive subject matter will
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`become more apparent from the following detailed description of preferred embodiments.
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`Brief Description of the Drawing
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`[0035] Figure | depicts an exemplary production process for the storage stable and low-dose
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`atropine ophthalmic formulation.
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`Detailed Description of the Invention
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`[0036] The inventive subject matter is directed to stable aqueous ophthalmic compositions of
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`atropine (and pharmaceutically acceptable salts thereof) in a ready-to-use form that are sterile
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`and preferably substantially free of preservatives. The stability of contemplated compositions
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`is characterized by low degradation of atropine to tropic acid at low atropine concentrations,
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`as well as by a physiologically desirable pH. For example, liquid and storage-stable low-dose
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`ophthalmic atropine compositions will typically have stability upon storage overat least two
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`months at 25 °C and 60% relative humidity such that equal or less than 0.35% tropic acid is
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`formed by the degradation of atropine in the formulation. Most preferably, the compositions
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`are also free of preservatives, and particularly benzalkonium chloride that is commonly used
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`as a preservative. Such stability is particularly unexpected where the atropine concentration
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`in the ophthalmic compositionis relatively low (e.g., 0.02 wi%) and where the composition
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`has arelatively high pH (e.g., between 5.0 and 6.0) as it was generally known that atropine
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`stability decreases at decreasing concentrations and increasing pH.
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`[0037] While not wishing to be bound by any particular theory or hypothesis, the inventors
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`contemplate that low buffer strength using a two-component buffer system at a pH near to a
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`neutral pH (such as pH 5.0-6.0) reduces hydrolysis of atropine to tropic acid where atropine
`
`concentrations are relatively low (e.g., equal or less than 0.05 wt%, or equal or less than 0.02
`
`wt%, or equal or less than 0.01 wt%). Unless indicated otherwise, all percentages are weight
`
`percentages (wt%) or expressed as weight by volume (w/v). Moreover, it is noted that weight
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`percentages of atropine sulfate provided herein are based on atropine sulfate monohydrate.
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`[0038] More specifically, and as is described in more detail below, the inventors discovered
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`that low-dose ophthalmic atropine compositions can be prepared with atropine in a ready-to-
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`use concentration (e.g., for treatment of myopia) that have a near-physiological pH, and that
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`preferably lack any preservative in the formulation. Surprisingly, the storage stability at two
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`months at 25 °C and 60% RH of the ophthalmic compositions presented herein is remarkably
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`high, with tropic acid formation from atropine hydrolysis in most cases at or below 0.35%, at
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`or below 0.30%, or at or below 0.28%. Similarly, contemplated formulations at accelerated
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`storage conditions over two months at 40 °C and 75% RH also exhibited an equally favorable
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`profile with tropic acid formation in most cases at or below 1.7%, at or below 1.5%, at or
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`below 1.3%, or at or below 1.2%.
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`[0039] Therefore, contemplated atropine formulations of the inventive subject matter can be
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`advantageously provided in a ready-to-use format that avoids the inconvenience associated
`
`with diluting concentrated atropine formulations into diluents prior to administration. Thus,
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`the ready-to-use formulations also eliminate microbial contamination risks and/or calculation
`
`errors associated with dilution. Most typically, contemplated formulations will be available
`
`In a range of concentrations commonly required by medical practitioners for treatment of
`
`myopia, and particularly pediatric myopia. Consequently, atropine will typically be present in
`
`formulations in an amount of equal or less than 0.05 wt%, or in an amount of equal or less
`
`than 0.02 wt%, or in an amount of equal or less than 0.01 wt%. For example, the atropine or
`
`a pharmaceutically acceptable salt thereof may be present in the ophthalmic composition in
`
`an amount of between 0.01% and 0.05 wt%, between 0.001 wt% and 0.02 wt%, or between
`
`0.001 wt% and 0.01 wt%. As will be readily appreciated, atropine for the preparation of
`
`contemplated formulations may be atropine or any suitable pharmaceutically acceptable salt
`
`thereof, including mineral salts (e.g., HCl salt) and organicsalts (e.g., sulfate). Similarly,
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`where desired, the atropine may also be used in any suitable prodrug form.
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`[0040] For example, in one exemplary embodiment, the concentration of atropine in
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`contemplated atropine formulations is from about 0.001% to about 0.05% (w/w); or from
`
`about 0.005% to about 0.045% (w/w), or from about 0.006% to about 0.035% (w/w), or from
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`about 0.007% to about 0.030% (w/w), or from about 0.008% to about 0.025% (w/w), or from
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`about 0.009% to about 0.022% (w/w), or from about